Cytokines exert their respective biochemical and physiological effects by binding to specific receptor molecules. Receptor binding then stimulates specific signal transduction pathways (Kishimoto et al., Cell 76:253-262, 1994). The specific interactions of cytokines with their receptors can be the primary regulators of a wide variety of cellular processes including activation, proliferation, and differentiation of cells (Arai et al., Ann. Rev. Biochem. 59:783-836, 1990; Paul and Seder, Cell 76:241-251, 1994).
IL-21 was isolated from a cDNA library derived from activated CD3 (+) T-cells (Parrish-Novak et al., Nature 408 57-63, 2000). The IL-21 cDNA encodes a secreted protein of 131 amino acids protein most closely related to IL-2 and IL-15. The IL-21 gene has been mapped to human chromosome 4q26-q27 near the IL-2 gene.
IL-21 mRNA is expressed in activated CD4+ but not in activated CD8+ T-cells. In addition, IL-21 was expression was not detected in B-cells and monocytes (Parrish-Novak et al., Nature 408:57-63, 2000). However, it has been demonstrated that IL-21 stimulates proliferation of B-cells that are stimulated by cross-linking of the CD40 antigen and proliferation stimulated by IL-4 in addition to anti-IgM. IL-21 has also been shown to stimulate proliferation of naive (CD45RA+) cells, but not memory (CD45RO+) T-cells, mediated by engagement of CD3. IL-21 has also been shown to stimulate the proliferation of bone marrow progenitor to cells and to enhance the expression of the NK-cell marker CD56 in the presence of IL-15 (for review, see Horst Ibelgaufts' COPE: Cytokines Online Pathfinder Encyclopaedia, available on the internet).
The IL-21 receptor has been isolated and was found to be expressed by CD23+ B-cells, B-cell lines, a T-cell leukemia line, and NK-cell lines. The receptor gene has been mapped to human chromosome 16p12 (see Parrish-Novak et al., Nature 408:57-63, 2000; Ozaki et al., Proc. Natl. Acad. Sci. USA 97:11439-11444, 2000).
The IL-21 receptor (IL-21R) is 538 amino acids, and is most closely related to human IL-2 receptor beta chain. The IL-21R forms heterodimers with the common cytokine receptor gamma chain, which is an indispensable subunit of the functional receptor complexes for IL-2, IL-4, IL-7, IL-9, and IL-15, and has been shown also to be part of the IL-21 receptor complex. The functional signaling complex activates has been demonstrated to activate the Janus kinase (Jak1, Jak3) and the Stat proteins (see Asao et al., J. Immunol. 167:1-5, 2000). However, the effects of IL-21 on B cell activity have not yet been fully elucidated.